1. Field of the Invention
The present invention relates to prodrugs of NAALADase inhibitors, pharmaceutical compositions comprising the same, and methods of using the same to treat glutamate abnormalities and prostate diseases.
2. Description of the Prior Art
Glutamate serves as the predominant excitatory neurotransmitter in the central nervous system (CNS) Neurons release glutamate in great quantities when they are deprived of oxygen, as may occur during an ischemic brain insult such as a stroke or a heart attack. This excess release of glutamate in turn causes over-stimulation (excitotoxicity) of N-methyl-D-aspartate (NMDA), AMPA, Kainate and MGR receptors. When glutamate binds to these receptors, ion channels in the receptors open, permitting flows of ions across their cell membranes, e.g., Ca2+ and Na+ into the cells and K+ out of the cells. These flows of ions, especially the influx of Ca2+, cause over-stimulation of the neurons. The over-stimulated neurons secrete more glutamate, creating a domino-effect which ultimately results in cell death via the production of proteases, lipases and free radicals.
Excessive activation of glutamate receptors has been implicated in various neurological diseases and conditions, including epilepsy, stroke, Alzheimer""s disease, Parkinson""s Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington""s Disease, schizophrenia, chronic pain, ischemia and neuronal loss following hypoxia, hypoglycemia, ischemia, trauma, and nervous insult. Recent studies have also advanced a glutamatergic basis for compulsive disorders, particularly drug dependence.
As an example, neurophysiological and pathological effects of ethanol have been found to be mediated through the glutamatergic system. Specifically, acute exposure to ethanol disrupts glutamatergic neurotransmission by inhibiting ion flow through channels in glutamate receptors, whereas chronic exposure up-regulates the number of glutamate receptors and thereby increases ion flow. Acute withdrawal from ethanol results in hyperexcitability and seizures in the presence of up-regulated channels, thereby making postsynaptic neurons vulnerable to excitotoxic damage.
Post mortem examinations of histologically normal brains from alcoholics have shown that chronic alcoholism moderately increases the density of the NMDA subtype of glutamate receptors in the frontal cortex. This up-regulation may represent a stage of ethanol-induced chronic neurotoxicity. As such, neurobiological effects of alcoholism, including intoxication, withdrawal seizures, delirium tremens, Wernicke-Korsakoff syndrome and fetal alcohol syndrome, can be understood as a spectrum of the consequences of ethanol""s effect on the glutamatergic system. In this regard, alcoholism may be considered another member of the expanding family of glutamate-related neurological disorders.
The glutamatergic system has also been implicated in the behavioral effects of other abused drugs. For example, studies have shown that glutamatergic antagonists block motor-stimulating activities induced by amphetamine and cocaine, and glutamatergic agonists cause the same stereotypy as that produced by amphetamine. These results represent pharmacological evidence that the expression of the stereotypic effect of psychomotor stimulants involves the glutamatergic system.
Epidemiologic studies have revealed a strong correlation between drug dependence and other compulsive disorders Additionally, a common genetic anomaly has been found among people with alcoholism, cocaine dependence, nicotine dependence, pathological gambling, attention deficit disorder (ADD), Tourette""s syndrome, compulsive overeating and obesity. Such disorders are believed to be manifestations of the effects of excitotoxicity.
Attempts to prevent excitotoxicity by blocking NMDA, AMPA, Kainate and MGR receptors have proven difficult because each receptor has multiple sites to which glutamate may bind. Many of the compositions that are effective in blocking the receptors are also toxic to animals. As such, there is currently no known effective treatment for glutate abnormalities.
Prostate cancer is the leading form of cancer and the second leading cause of death from cancer for men in the United States. The American Cancer Society has estimated that in 1996 alone, 317,100 new cases of prostate cancer were diagnosed and 41,400 deaths were caused by prostate cancer. The incidence rate of prostate cancer increased 65% between 1980 and 1990, and will continue to rise with improved screening tests and longer life expectancies. While most men used to die of other illnesses before prostate cancer had a chance to develop, higher prostate cancer mortality rates are expected as men live longer and the disease has more time to progress.
In 1993, the molecular cloning of Prostate Specific Membrane Antigen (PSMA) was reported as a potential prostate carcinoma marker and hypothesized to serve as a target for imaging and cytotoxic treatment modalities for prostate cancer. PSMA antibodies, particularly indium-111 labelled and itrium labelled PSMA antibodies, have been described and examined clinically for the diagnosis and treatment of prostate cancer. PSMA is expressed in prostatic ductal epithelium and is present in seminal plasma, prostatic fluid and urine. In 1996, it was found that the expression of PSMA cDNA confers the activity of NAALADase.
NAAG and NAALADase have been implicated in several human and animal pathological conditions. For example, it has been demonstrated that intra-hippocampal injections of NAAG elicit prolonged seizure activity. More recently, it was reported that rats genetically prone to epileptic seizures have a persistent increase in their basal level of NAALADase activity. These observations support the hypothesis that increased availability of synaptic glutamate elevates seizure susceptibility, and suggest that NAALADase inhibitors may provide anti-epileptic activity.
NAAG and NAALADase have also been implicated in the pathogenesis of ALS and in the pathologically similar animal disease called Hereditary Canine Spinal Muscular Atrophy (HCSMA). It has been shown that concentrations of NAAG and its metabolitesxe2x80x94NAA, glutamate and aspartatexe2x80x94are elevated two- to three-fold in the cerebrospinal fluid of ALS patients and HCSMA dogs. Additionally, NAALADase activity is significantly increased (two- to three-fold) in post-mortem spinal cord tissue from ALS patients and HCSMA dogs. As such, NAALADase inhibitors may be clinically useful in curbing the progression of ALS if increased metabolism of NAAG is responsible for the alterations of CSF levels of these acidic amino acids and peptides.
Abnormalities in NAAG levels and NAALADase activity have also been documented in post-mortem schizophrenic brain, specifically in the prefrontal and limbic brain regions.
The findings described above suggest that NAALADase inhibitors could be useful in treating glutamate abnormalities. In fact, the results of studies conducted by the inventors confirm that NAALADase inhibitors are effective in treating glutamate abnormalities (particularly stroke, Parkinson""s Disease, Amyotrophic Lateral Sclerosis (ALS), spinal cord injury, alcoholism and nicotine dependence), as well as prostate diseases (particularly prostate cancer).
While a few NAALADase inhibitors have been identified, they have only been used in non-clinical research. Examples of such inhibitors include general metallopeptidase inhibitors such as o-phenanthroline, metal chelators such as EGTA and EDTA, and peptide analogs such as quisqualic acid and xcex2-NAAG. Accordingly, a need exists for new NAALADase inhibitors, as well as pharmaceutical compositions and methods using such new and known NAALADase inhibitors to treat glutamate abnormalities and prostate diseases. Furthermore, there is a need for prodrugs of such NAALADase inhibitors to optimize pharmaceutical, pharmacokinetic and pharmacodynamic activity.
The present invention relates a prodrug of a NAALADase inhibitor.
In a preferred embodiment, the NAALADase inhibitor is a glutamate-derived hydroxyphosphinyl derivative of formula I: 
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
X is CR3R4, O or NR5;
R1 and R5 are independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein said R1 and R5 are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar, and halo;
R2 is selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar, wherein said R2 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzyl and phenyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino.
In another preferred embodiment, the prodrug is a compound of formula II 
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
X is CR5R6, NR7 or O;
R1 and R7 are independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar1, wherein said R1 and R7 are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2;
R2 is selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar1, wherein said R2 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2;
R3 and R4 are independently selected from the group consisting of hydrogen, carboxy, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, and Ar1, provided that both R3 and R4 are not hydrogen; wherein said R3 and R4 are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, amino, and Ar2;
R5 and R6 are independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, and halo;
Ar1 and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzyl and phenyl, wherein said Ar1 and Ar2 are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino.
Additionally, the present invention relates to a pharmaceutical composition comprising:
(i) an effective amount of a prodrug of a NAALADase inhibitor; and
(ii) a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a glutamate abnormality in an animal, comprising administering an effective amount of a prodrug of a NAALADase inhibitor to said animal.
Furthermore, the present invention relates to a method of effecting a neuronal activity in an animal, comprising administering an effective amount of a prodrug of a NAALADase inhibitor to said animal.
Additionally, the present invention relates to a method of treating a compulsive disorder, comprising administering an effective amount of a prodrug of a NAALADase inhibitor to a patient in need thereof.
Finally, the present invention relates to a method of treating a prostate disease in an animal, comprising administering an effective amount of a prodrug of a NAALADase inhibitor to said animal.